Mechanisms Of Ammonia Activation And Ammonium Ion Inhibition Of ...

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Abstract

The mechanism of methanol oxidation by quinoprotein methanol dehydrogenase (MDH.PQQ) in combination with methanol (MDH.PQQ.methanol) involves Glu-171--CO2(-) general base removal of the hydroxyl proton of methanol in concert with hydride equivalent transfer to the >C5=O quinone carbon of pyrroloquinoline quinone (PQQ) and rearrangement to hydroquinone (PQQH2) with release of formaldehyde. Molecular dynamics (MD) studies of the structures of MDH.PQQ.methanol in the presence of activator NH3 and inhibitor NH4(+) have been carried out. In the MD structure of MDH.PQQ.methanol.NH3, the hydrated NH3 resides at a distance of approximately 24 A away from methanol and the ortho-quinone portion of PQQ. As such, influence of NH3 on the oxidation reaction is not probable. We find that NH4(+) competes with the substrate by hydrogen-bonding to Glu-171CO2(-) such that the MDH.PQQ.methanol.NH4(+) complex is not reactive. Ammonia readily forms imines with quinone. Imines are present in solution as neutral (>C5=NH) and protonated (>C5=NH2(+)) species. MD simulations establish that the >C5=NH2(+) derivative of MDH.PQQ(NH2(+).methanol structure is unreactive because of the nonproductive means of methanol binding. The structure obtained by the MD simulations with the neutral >C5=NH imine of MDH.PQQ(NH).methanol structure is similar to the reactive MDH.PQQ.methanol complex. This active site geometry allows for catalysis of hydride equivalent transfer to the >C5=NH of PQQ(NH) by concerted Glu-171CO(2)(-) general-base removal of the H-OCH3 proton and Arg-324H+ general-acid proton transfer to the imine nitrogen. Enzyme-bound <C5(H)NH2 derivative of PQQ [PQQ(NH)] and CH(2)O product are formed.

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Figures

Fig. 1.

Fig. 1.

Structure of the PQQ ( …

Fig. 1.

Structure of the PQQ ( a ), modified PQQ, formula image ( b ), and…

Fig. 1. Structure of the PQQ (a), modified PQQ, formula image (b), and PQQ(NH) (c).
Fig. 2.

Fig. 2.

Hydride transfer mechanism (from MD…

Fig. 2.

Hydride transfer mechanism (from MD studies) of methanol oxidation by the MDH.

Fig. 2. Hydride transfer mechanism (from MD studies) of methanol oxidation by the MDH.
Fig. 3.

Fig. 3.

Active site residues in the…

Fig. 3.

Active site residues in the MD-averaged structures: MDH·PQQ·methanol ( a ), MDH·PQQ·methanol·NH 3 …

Fig. 3. Active site residues in the MD-averaged structures: MDH·PQQ·methanol (a), MDH·PQQ·methanol·NH3 (b), formula image (c), formula image (d), and MDH·PQQ(NH)·methanol (e). Ca2+ is omitted for clarity. Nonbonded interactions are shown by dashed lines. Distances between the heavy atoms are in Å.
Fig. 4.

Fig. 4.

Ca 2+ coordination in the…

Fig. 4.

Ca 2+ coordination in the MD-averaged structures: MDH·PQQ·methanol ( a ), MDH·PQQ·methanol·NH 3 …

Fig. 4. Ca2+ coordination in the MD-averaged structures: MDH·PQQ·methanol (a), MDH·PQQ·methanol·NH3 (b), formula image (c), formula image (d), and MDH·PQQ(NH)·methanol (e). Distances are in Å.
Fig. 5.

Fig. 5.

Active site residues in the…

Fig. 5.

Active site residues in the MD-averaged intermediate structures: MDH·PQQH ( a ) and formula image …

Fig. 5. Active site residues in the MD-averaged intermediate structures: MDH·PQQH (a) and formula image (b). Ca2+ is omitted for clarity. Nonbonded interactions are shown by dashed lines. Distances between the heavy atoms and those involving hydrogen atoms (in brackets) are in Å.
Fig. 6.

Fig. 6.

Time-dependent variation of distances between…

Fig. 6.

Time-dependent variation of distances between the methanol oxygen and carboxylate oxygen (OE1) of…

Fig. 6. Time-dependent variation of distances between the methanol oxygen and carboxylate oxygen (OE1) of Glu-171formula imageformula image (a), C5 quinone carbonyl carbon of PQQ and methanol carbon (b), methanol oxygen and carboxylate oxygen (OD1) of Asp-297formula imageformula image (c), and C5 carbon of PQQ and methanol oxygen of MDH·PQQ(NH)·methanol (d) structures. The dotted line corresponds to the separation of methanol hydroxyl hydrogen and OE1 of Glu-171formula imageformula image (a) and OD1 of Asp-297formula imageformula image (c).
Fig. 7.

Fig. 7.

Stereoview of the active site…

Fig. 7.

Stereoview of the active site depicting important interactions of the MD-averaged (2.025–4.0 ns)…

Fig. 7. Stereoview of the active site depicting important interactions of the MD-averaged (2.025–4.0 ns) MDH·PQQ(NH)·methanol structure. The methanol carbon is colored cyan. The Ca2+ coordination is in green, and coordinating distances are omitted for clarity and given in Fig. 4e. Nonbonded interactions are shown as red dashed lines. Average distances between heavy atoms are given in Å.
All figures (7) See this image and copyright information in PMC

References

    1. Anthony, C. (1986) Adv. Microbiol. Physiol. 27, 113–210. - PubMed
    1. Duine, J. A. (1991) Eur. J. Biochem. 200, 271–284. - PubMed
    1. Anthony, C. (1996) Biochem. J. 320, 697–711. - PMC - PubMed
    1. Davidson, V. L. (2001) Adv. Protein Chem. 58, 95–140. - PubMed
    1. Anthony, C. (2004) Arch. Biochem. Biophys. 428, 2–9. - PubMed
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